Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease with an estimated minimum incidence of 1 in 8000 (Harper, P. S., Myotonic Dystrophy, 2nd ed., W. B. Saunders Co., London, 1989). It is the most common form of muscular dystrophy affecting adults. The clinical picture in DM is well established but exceptionally variable (Harper, P. S., Myotonic Dystrophy, 2nd ed., W. B. Saunders Co., London, 1989). Although generally considered a disease of muscle, with myotonia, progressive weakness and wasting, DM is characterized by abnormalities in a variety of other systems. DM patients often suffer from cardiac conduction defects, smooth muscle involvement, hypersomnia, cataracts, abnormal glucose response, and, in males, premature balding and testicular atrophy (Harper, P. S., Myotonic Dystrophy, 2nd ed., W. B. Saunders Co., London, 1989). One of the striking features of this disorder is the variability of phenotype, both within and between families. For clinical purposes, patients are often subdivided into three groups according to the clinical syndrome and age at onset of the disorder (Harper, P. S. and Dyken, P. R., Lancet, 2:53-55 (1972)). The mildest form, which is occasionally difficult to diagnose, is seen in middle or old age and is characterized by cataracts with little or no muscle involvement. The classical form, showing myotonia and muscle weakness, most frequently has onset in early adult life and in adolescence. The most severe form, which occurs congenitally, is associated with generalized muscular hypoplasia, mental retardation, and high neonatal mortality. Those congenitally affected offspring surviving the neonatal period invariably exhibit the classical form of the disease in late childhood or adolescence. The congenital form of DM is almost exclusively maternally transmitted. The phenomenon of anticipation (Howeler, C. J. et al., Brain, 112:779-797 (1989)), in which the disease symptoms become more severe and age at onset earlier in successive generations, is often most strikingly manifested in a family producing a congenitally affected child.
To date this disease has been untreatable and its biochemical basis is not understood. Biochemical studies have failed to identify the defective protein in myotonic dystrophy, although several have implicated defects in membrane structure and function (Harper, P. S., Myotonic Dystrophy, 2nd ed., W. B. Saunders Co., London, 1989). Abnormalities in calcium transport (Seiler, D. and Kuhn, E., Schweitz Med. Wochenschr. 100:1374-1376 (1970)), membrane fluidity (Butterfield, D. A. et al., Biochemistry, 13:5078-5082 (1974)), sodium-potassium ATPase stoichiometry (Hull, K. L., Jr. and Roses, A. D., J. Physiol., 254:169-181 (1976)), and apamin receptor expression (Renaud, J. F. et al., Nature 319:676-680 (1986)) have all been reported for DM. There is also evidence of reduced phosphorylation of membrane proteins in both red blood cells (Roses, A. D. and Appel, S. H., Proc. Natl. Acad. Sci. USA 70:1855-1859 (1973)) and sarcolemmal membranes from muscle biopsies of patients (Roses, A. D. and Appel, S. H., Nature 250:245-247 (1974)).
A better understanding of the underlying mechanism of DM would be very valuable in diagnosing and, ultimately, treating or preventing DM.